Anthracyclines are widely accepted as some of the most effective anti-cancer drugs (Weiss (1992), Semin. Oncol. 19:670-686). Nevertheless, clinical use of the anthracyclines doxorubicin (Dox) and daunorubicin (DNR) have proven to be hampered by side effects such as the development of resistance in tumor cells or toxicity in healthy tissues, most notably chronic cardiomyopathy and congestive heart failure (CHF). To avoid the latter, the maximum recommended cumulative dosages of DNR and Dox were tentatively set at 500 or 450 to 600 mg/m2, respectively. Furthermore, there have been numerous attempts to identify novel anthracyclines that prove superior to DOX or DNR in terms of activity and/or cardiac tolerability. Unfortunately, few have reached the stage of clinical development and approval. Additional anthracyclines that have been approved for clinical use include epirubicin, idarubicin, pirarubicin, aclarubicin, and mitroxantrone (Minotti et al. (2004), Pharmacol. Rev. 56:185-229).
Doxorubicin is the most commonly used anthracycline in the treatment of hematological and solid malignancies. Doxorubicin-induced cardiomyopathy may be divided into acute, subacute, and late forms (Bristow et al. (1978), Cancer Treat. Rep. 62:873-879). The acute form is myocarditis/pericarditis syndrome that starts within 24 hours of the infusion and is not associated with poor long-term prognosis. Minor effects are picked up on the electrocardiogram (EKG) but in most cases resolve without any major problems. Subacute toxicity ensues weeks after Doxorubicin treatment but may be seen as late as 30 months. This form is associated with chronic changes and mortality may be as high as 60% (Goorin et al. (1981), Cancer, 47:2810-2816). Chronic toxicity may be evident as late as 4 to 20 years after the treatment with doxorubicin. It is accompanied by clinical heart failure and echocardiographic and pathologic changes.
Chronic cardiac changes that are due to doxorubicin appear to be irreversible, and the prognosis with doxorubicin-induced cardiomyopathy seems to be very poor without cardiac replacement therapy. Several agents have been employed for the attenuation of cardiomyopathic damaged induced by doxorubicin and include anti-oxidants, angiotensin converting enzyme inhibitors, and dexrazoxane. However, none have yet gained sufficient proof of efficacy to justify a routine use. It appears the only reliable medical treatment of this condition is its prevention (Hamed et al. (2006), Eur. Heart J. 27:1876-1883; Simsir et al. (2005), Ann. Thorac. Surg., 80:717-719).
The ultrastructural features of anthracycline-induced cardiomyopathy, characterized in patients' endomyocardial biopsies, include the loss of myofibrils, dilation of the sarcoplasmic reticulum, cytoplasmic vacuolization, swelling of mitrochondria, and increased number of lysosomes. When severe, it leads to CHF.
Aries et al. (Proc. Natl. Acad. Sci. (2004), 101:6975-6980) showed that cardiotoxicity induced by Dox administration is correlated with a decrease in expression of the GATA-4 transcription factor, resulting in cardiomyocyte apoptosis. Aries et al. stated the results indicate that GATA-4 is an anti-apoptotic factor required for the adaptive stress response of the adult heart and suggests that use of α1-agonists in combination therapy with Dox may be beneficial to patients undergoing chemotherapy.
However, α1A-AR agonists are well known to effect an increase in blood pressure. Indeed, α1-AR agonists, such as phenylephrine and methoxamine, are marketed as drugs to treat hypotension. Thus, while administration of alpha1-agonists to patients receiving Dox treatment may reduce or prevent cardiotoxicity, such treatment may result in a detrimental increase of blood pressure in the patient.
It has been surprisingly discovered that the compound N-[5-(4,5-Dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide (known as A61603), when administered at an appropriate dose to a mammal undergoing Dox treatment, can provide beneficial reduction in cardiotoxicity without increasing blood pressure.